Utilization of the calcium channel blocker nimodipine in affective disorders is based on several empirical and theoretical rationales. The L-type calcium channel blocker verapamil has been reported effective in the treatment of acute mania but not depression, and nimodipine has a different profile of effects compared with verapamil. Nimodipine is: more lipid soluble; blocks cocaine-induced hyperactivity, sensitization, and dopamine overflow; blocks adenosine transporters and A1 receptors; and also has anticonvulsant effects in some models. Positive response to nimodipine has been observed in 9/22 (41%) of the evaluable patients, including those with rapid an ultradian cycling disorder. In four instances this was confirmed in an off-on-off-on (B-A-B-A) design. In combination therapy a more complete response was achieved with the blind addition of carbamazepine (CBZ) in 5/9 patients. Since CBZ has recently been described to inhibit calcium influx through the NMDA receptor, these data raise the possibility that drugs with differential effects on calcium (or other mechanisms) may be useful in combination in refractory patients. Three responders to nimodipine failed to achieve a blind crossover to verapamil but did show a sustained response to isradipine, suggesting that the dehydroxypyridine L-type calcium channel blockers may be differentially more effective than the diphenylalkylamine verapamil. A series of patients with recurrent brief depression (RBD) have responded dramatically to the blind institution of nimodipine. Nimodipine highly significantly increased CSF somatostatin in 21 patients, while it tended to decrease TRH; i.e., effects opposite those of CBZ. These data suggest the importance of further exploring the clinical profile of nimodipine in refractory affective disorders and examining the role of altered calcium metabolism and increases in somatostatin in relationship to nimodipine response. The increased intracellular accumulation of intracellular Ca++ in the blood element of affectively ill patients is being studied for both its mechanistic implications and to see if it would help predict which patients would be responsive to calcium-active therapeutic strategies.